A common pathway in many human disease states is microglia-mediated inflammation. Microglia are tissue-resident macrophages found in the retina and the central nervous system. Microglial cells constitute about ten to twenty percent of the cells in the adult brain. Under normal conditions, these cells are constitutively suppressed by endogenous cortisol. The cells become activated in the form of phagocytes and cytotoxic cells in the presence of a variety of stimuli. These stimuli include trauma, infection, inflammation, ischemia, lipopolysaccharides, reactive oxygen species, and damaged cell membranes. Once microglia are activated, they can migrate and recruit other microglia to the original site of damage. Malfunctioning cells can be killed by the release of tumor necrosis factor alpha (TNF-α), reactive oxygen species (ROS), and proteases. The resulting cell debris is phagocytized by the microglia cells.
Secondary cell damage occurs in a process referred to as bystander lysis: nearby healthy cells are destroyed in the toxic extracellular milieu created by the activated microglia. This amplifies the cell damage beyond the cells affected by the underlying pathologic event, and turns the remedy—the activated microglial cells—into a pathologic system in its own right.
The cascading pattern of primary pathology, response by microglial cells, and subsequent secondary pathology has been observed in a broad range of human diseases, including diseases of the eye. An essential element of sight is a functioning retina. The retina can be likened to the “film” of the eye. It converts light rays into electrical signals and sends them to the brain through the optic nerve. The sides of the retina are responsible for peripheral vision. The center area, called the macula, is used for fine central vision and color vision. The retina is where many problems leading to vision loss occur. Three of the leading causes of blindness due to retina damage associated with neuroninflammation are retinitis pigmentosa, macular degeneration and diabetic retinopathy, the leading cause of blindness in African Americans is glaucoma a degenerative process of the optic nerve and retina that involves neuroinflammation and microglial cell activation within the optic nerve that connects the retina to the brain. Other important retinal diseases that are associated with neuroinflammation include uveitis, auto-immune photoreceptor degenerations and infection.
From a clinical perspective, retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration have significant impact on human health and quality of life. Nine million Americans suffer progressive vision loss due to retinal neurodegenerative diseases. Retinitis pigmentosa affects one in four thousand individuals. It is the fourth leading cause of visual disability in the United States, after diabetic retinopathy, age-related macular degeneration, and glaucoma.
Age-related macular degeneration (AMD) is a neurodegenerative, neuroinflammatory disease of the macula, which is responsible for central vision loss. AMD is the leading cause of vision loss in people over age 65. Eight million people are legally blind from macular degeneration worldwide, and as the population ages this number is expected to grow
The pathogenesis of age-related macular degeneration involves chronic neuroinflammation in the choroid (a blood vessel layer under the retina), the retinal pigment epithelium (RPE), a cell layer under the neurosensory retina, Bruch's membrane and the neurosensory retina, itself. The disease first manifests as a dry form that involves the accumulation of drusen—cell debris and inflammatory material that form small masses within the RPE and Bruch's membrane. Drusen contain broken down cell membranes and other cell fragments and are highly antigenic, activating a localized microglial and macrophage-mediated inflammatory response within the retina. Over time, the toxic mediators associated with this inflammation break down Bruch's membrane and the RPE and can lead directly to vision loss or may lead to the leakage of vascular endothelial-derived growth factor from the choroidal circulation into the subretinal space. This, in turn, can lead to the formation of abnormal blood vessels, called choroidal neovascularization. Since these blood vessels are abnormal, they often leak serum, causing retina exudates and can sometimes bleed. Since fluid is involved, this is called, “wet” age-related macular degeneration. The “wet” and “dry” forms of age-related macular degeneration can co-exist, both involving neuroinflammation.
The microglial-mediated pathology is also common to a variety of central nervous system neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and acute spinal cord trauma. Brain injury is another cause of lifelong disability. For example, brain injury in the perinatal period can lead to cerebral palsy, which also involves microglial cells in the peri-ventricular leukomalacia following the injury.
There is a strong and immediate need in the art for clinically effective treatments for all these diseases, and inhibiting the common pathway of microglial-mediated tissue destruction as provided by the present disclosure meets this need.